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Single-cell RNA-sequencing identifies disease-associated oligodendrocytes in male APP NL-G-F and 5XFAD mice.

ABSTRACT: Alzheimer's disease (AD) is associated with progressive neuronal degeneration as amyloid-beta (Aβ) and tau proteins accumulate in the brain. Glial cells were recently reported to play an important role in the development of AD. However, little is known about the role of oligodendrocytes in AD pathogenesis. Here, we describe a disease-associated subpopulation of oligodendrocytes that is present during progression of AD-like pathology in the male App^NL-G-F and male 5xFAD AD mouse brains and in postmortem AD human brains using single-cell RNA sequencing analysis. Aberrant Erk1/2 signaling was found to be associated with the activation of disease-associated oligodendrocytes (DAOs) in male App^NL-G-F mouse brains. Notably, inhibition of Erk1/2 signaling in DAOs rescued impaired axonal myelination and ameliorated Aβ-associated pathologies and cognitive decline in the male App^NL-G-F AD mouse model.

SUBMITTER: Park H

PROVIDER: S-EPMC9925742 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Single-cell RNA-sequencing identifies disease-associated oligodendrocytes in male APP NL-G-F and 5XFAD mice.

Park Hanseul H Cho Byounggook B Kim Hongwon H Saito Takashi T Saido Takaomi C TC Won Kyoung-Jae KJ Kim Jongpil J

Nature communications 20230213 1

Alzheimer's disease (AD) is associated with progressive neuronal degeneration as amyloid-beta (Aβ) and tau proteins accumulate in the brain. Glial cells were recently reported to play an important role in the development of AD. However, little is known about the role of oligodendrocytes in AD pathogenesis. Here, we describe a disease-associated subpopulation of oligodendrocytes that is present during progression of AD-like pathology in the male App<sup>NL-G-F</sup> and male 5xFAD AD mouse brains ...[more]

PMID: 36781874

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Project description:BACKGROUND:The ?-secretase, BACE1, cleaves APP to initiate generation of the ?-amyloid peptide, A?, that comprises amyloid plaques in Alzheimer's disease (AD). Reducing BACE1 activity is an attractive therapeutic approach to AD, but complete inhibition of BACE1 could have mechanism-based side-effects as BACE1-/- mice show deficits in axon guidance, myelination, memory, and other neurological processes. Since BACE1+/- mice appear normal there is interest in determining whether 50% reduction in BACE1 is potentially effective in preventing or treating AD. APP transgenic mice heterozygous for BACE1 have decreased A? but the extent of reduction varies greatly from study to study. Here we assess the effects of 50% BACE1 reduction on the widely used 5XFAD mouse model of AD. RESULTS:50% BACE1 reduction reduces A?42, plaques, and BACE1-cleaved APP fragments in female, but not in male, 5XFAD/BACE1+/- mice. 5XFAD/BACE1+/+ females have higher levels of A?42 and steady-state transgenic APP than males, likely caused by an estrogen response element in the transgene Thy-1 promoter. We hypothesize that higher transgenic APP level in female 5XFAD mice causes BACE1 to no longer be in excess over APP so that 50% BACE1 reduction has a significant A?42 lowering effect. In contrast, the lower APP level in 5XFAD males allows BACE1 to be in excess over APP even at 50% BACE1 reduction, preventing lowering of A?42 in 5XFAD/BACE1+/- males. We also developed and validated a dot blot assay with an A?42-selective antibody as an accurate and cost-effective alternative to ELISA for measuring cerebral A?42 levels. CONCLUSIONS:50% BACE1 reduction lowers A?42 in female 5XFAD mice only, potentially because BACE1 is not in excess over APP in 5XFAD females with higher transgene expression, while BACE1 is in excess over APP in 5XFAD males with lower transgene expression. Our results suggest that greater than 50% BACE1 inhibition might be necessary to significantly lower A?, given that BACE1 is likely to be in excess over APP in the human brain. Additionally, in experiments using the 5XFAD mouse model, or other Thy-1 promoter transgenic mice, equal numbers of male and female mice should be used, in order to avoid artifactual gender-related differences.

Project description:As the proportion of elderly in society increases, so do the number of older patients undergoing surgical procedures. This is concerning as exposure to anesthesia has been identified as a risk factor for Alzheimer's disease (AD). However, the causal relationship between clinical AD development and anesthesia remains conjectural. Preclinical studies have demonstrated that anesthesia, such as halothane, isoflurane, and sevoflurane, induces AD-like pathophysiological changes and cognitive impairments in transgenic mouse models of AD. Desflurane does not have these effects and is expected to have more potential for use in elderly patients, yet little is known about its effects, especially on non-cognitive functions, such as motor and emotional functions. Thus, we examined the postanesthetic effects of desflurane and sevoflurane on motor and emotional function in aged AppNL-G-F/NL-G-F (App-KI) mice. This is a recently developed transgenic mouse model of AD exhibiting amyloid β peptide (Aβ) amyloidosis and a neuroinflammatory response in an age-dependent manner without non-physiological amyloid precursor protein (APP) overexpression. Mice were subjected to a short behavioral test battery consisting of an elevated plus maze, a balance beam test, and a tail suspension test seven days after exposure to 8.0% desflurane for 6 h or 2.8% sevoflurane for 2 h. App-KI mice showed significant increments in the percentage of entry and time spent in open arms in the elevated plus maze, increments in the number of slips and latency to traverse for the balance beam test, increments in the limb clasping score, increments in immobile duration, and decrements in latency to first immobile episode for the tail suspension test compared to age-matched wild type (WT) controls. Desflurane- and sevoflurane-exposed App-KI mice showed a delayed decrement in the number of slips for each trial in the balance beam test, while air-treated App-KI mice rapidly improved their performance, and increased their clasping behavior in the tail suspension test. Furthermore, App-KI inhibited the change in membrane GluA3 following exposure to anesthetics in the cerebellum. These results suggest high validity of App-KI mice as an animal model of AD.

Dataset Information

Single-cell RNA-sequencing identifies disease-associated oligodendrocytes in male APP NL-G-F and 5XFAD mice.

Publications

Single-cell RNA-sequencing identifies disease-associated oligodendrocytes in male APP NL-G-F and 5XFAD mice.

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